The invention is directed to a calibration fluid for a calibration of a sensor for measuring a blood value, an application of the fluid and a method for the production of the fluid.
EP 0 657 030 B1 discloses a calibration fluid for a calibration of a sensor for measuring a blood value that comprises a biocompatible electrolyte that, for example, is composed of a Ringer, Ringer Lactate or Ringer Acetate infusion solution and a biocompatible carbon dioxide source that is added to this solution, this generating bicarbonate ions (HCO3xe2x88x92ions) in a specific concentration and carbon dioxide (CO2) with a specific partial pressure pCO2 in the solution.
The compositions of biocompatible electrolytes employed as infusion solutions can be derived from the product descriptions of the various pharmaceutical companies such as, for example, Pharmacia, Braun, Fresenius, Baxter, etc. The composition of blood or blood plasma in view of the pH value, carbon dioxide partial pressure pCO2 and concentrations of the ions contained in the blood is described, for example, in Koryta, xe2x80x9cMedical and Biological Applications of Electrochemical Devicesxe2x80x9d, John Wiley and Sons, 1980, page 82.
Given a specific example of the calibration fluid according to EP 0 657 030 B1 (see page 4, lines 2-7 therein), the fluid is composed of 500 ml Ringer Lactate solution to which 10 ml of 8.4% NaHCO3 are added as carbon dioxide source. The added quantity of NaHCO3 corresponds to approximately 20 mmol/l that is contained in the Ringer lactate solution and temporarily stabilizes the unstable pH value of such a solution.
HCO3xe2x88x92 ions are not contained in traditional physiological electrolytes such as Ringer solutions but are contained in blood plasma. The normal physiological concentration of the HCO3xe2x88x92 ions in blood plasma lies at 24 mmol/l and can fluctuate within a concentration range containing this concentration value that is still viewed as being physiologically normal.
Given the specific example of the calibration fluid according to EP 0 657 030 B1, the 20 mmol/l NaHCO3 added to the original electrolyte free of HCO3xe2x88x92 ions generate HCO3xe2x88x92 ions in the electrolyte in a concentration that still lies in the normal physiological range of the concentration of the HCO3xe2x88x92 ions in blood plasma at 37xc2x0 C.
In the specific example of the calibration fluid according to EP 0 657 030 B1, the concentration of the HCO3xe2x88x92 ions at 37xc2x0 C. is so high that this fluidxe2x80x94according to the known Henderson-Hasselbalch equation (see, for example, Muller-Plathe, xe2x80x9cSxc3xa4ure-Basen-Haushalt und Blutgasexe2x80x9d, Thieme Verlag, 1982, for example page 32)xe2x80x94has a pH value of 7.95 at this temperature and a value of the pCO2 of 1.2xc2x7103 Pa (=9 mmHg), these values remaining stable, for example, over a time span of 18 hours.
The pH value of the fluid can be lowered to approximately 7.1 by adding another agent for regulating the pH value, for example sodium or potassium phosphate, so that it is possible to hold the pCO2 to more than 7.33xc2x7103 Pa (=55 mmHg). In this case, however, there is no longer a fluid according to the preamble of claim 1, since the concentration of the HCO3xe2x88x92 ions does not lie in the normal physiological range of this concentration, for example in the range 24 mmol/lxc2x15 mmol/l.
The normal physiological pH value of blood, which is recited as 7.41 at 37xc2x0 C. in many medical textbooks, falls into the pH range between 7.1 and 7.95.
Biocompatible or, respectively, physiological electrolytes such as Ringer solutions are often stored in plastic bags and are air-saturated. At 22xc2x0 C. and 760xc2x7(4/3)xc2x7102 Pa (760 mmHg) air pressure, a partial pressure composition for this electrolyte derives as
155xc2x7(4/3)xc2x7102 Pa (155 mmHg) pO2 
585xc2x7(4/3)xc2x7102 Pa (585 mmHg) pN2 
20xc2x7(4/3)xc2x7102 Pa (20 mmHg) pH2O, i.e.
760xc2x7(4/3)xc2x7102 Pa (760 mmHg).
overall
pO2 is thereby the partial pressure of the oxygen, pN2 is the partial pressure of the nitrogen and pH2O is the partial pressure of water.
By adding the 20 mmol/l NaHCO3 to such an electrolyte, 9xc2x7(4/3)xc2x7102 Pa (9 mmHg) pCO2 is added to the sum of these partial pressures orxe2x80x94given the presence of the inorganic phosphate bufferxe2x80x9455xc2x7(4/3)xc2x7102 Pa (55 mmHg) pCO2 is added thereto. The atmospheric pressure that is respectively present and bears on the fluid is thereby exceeded, and an exhalation of gases of the fluid, i.e. a bubble formation in the fluid, can occur.
Physiological electrolytes such as Ringer solutions exhibit an ion intensity that is usually equal to the normal physiological ion intensity of blood, this lying at 155 mmol/l and potentially fluctuating within an ion intensity range containing this ion intensity value that is still considered physiologically normal.
The addition of the 20 mmol/l NaHCO3 to such an electrolyte raises the ion intensity of the calibration fluid resulting therefrom by 20 mmol/l to non-physiological values that, for example, lie between 165 mmol/l and 185 mmol/l.
In physiological electrolytes such as Ringer solutions, moreover, the concentration of Na+ ions is usually selected equal to the normal physiological concentration of the blood, this lying at 140 mmol/l. The addition of the 20 mmol/l NaHCO3 to the electrolyte increases the concentration of the Na+ ions in the calibration fluid resulting therefrom from the normal 140 mmol/l to non-physiological 160 mmol/l.
Moreover, physiological electrolytes such as Ringer solutions comprise an osmolarity that is selected equal to the normal physiological osmolarity of blood plasma, this lying at 295 mosmol/l and potentially fluctuating within an osmolarity range containing this osmolarity value that is still considered physiologically normal.
The addition of the 20 mmol/l NaHCO3 to such an electrolyte raises the osmolarity of the calibration fluid resulting therefrom by 2xc2x720 mosmol/l=40 mosmol/l to non-physiological values that, for example, lie between 315 mosmol/l and 355 mosmol/l.
The known calibration fluid can be infused, and sensors for measuring the pCO2 of blood can be calibrated with this fluid not only in vitro but also in vivo.
An object of the invention is to offer calibration fluid that enables a calibration of the sensor with a precision that is higher compared to the known calibration fluid.
This object is achieved by the calibration fluid compose of a bio-compatible electrolyte that at 37xc2x0 C. has a concentration of bicarbonate ions that lies in a range of 24 mmol/lxc2x15 mmol/l, a pH value that lies in a pH range within 5 through 9 and contains a value of 7.41; and an ion intensity that lies in a range of 155 mmol/lxc2x110 mmol/l.
The normal physiological range of the concentration of bicarbonate ions blood plasma falls in the range of 25 mmol/lxc2x15 mmol/l of the concentration of the bicarbonate ions indicated in claim 1, and the normal physiological range of the ion intensity (ionic strength) of the blood falls in the recited range of 155 mmol/lxc2x110 mmol/l, and it can be expedient to select a value lying optimally close to 155 mmol/l for the concentration of the bicarbonate ions and to select a value lying optimally close to 155 mmol/l for the ion intensity.
The specific example of a calibration fluid known from EP 0 657 030 B1 and the inventive calibration fluid differ essentially in that the ion intensity in the known calibration fluidxe2x80x94differing from the inventive calibration fluidxe2x80x94does not lie in the range of 155 mmol/lxc2x110 mmol/l but outside this range.
The inventive calibration fluid is based on the perception resulting from Nernst""s equation (see Koryta, pages 13 ff) that, given potentiometric determination of the unknown pH value and/or of an unknown concentration of an ion type of a fluid such as, for example, blood with the assistance of a fluid having a known pH value and/or of a known concentration of this ion typexe2x80x94the concentrations of the two fluids can only be directly compared to one another and a correct concentration result with respect to the unknown fluid can only be obtained with the ion intensities of the two fluids are at least approximately equal to one another from the very outset.
Since the ion intensity given the inventive calibration fluid lies in the range 155 mmol/xc2x110 mmol/l, this fluid exhibits essentially the same ion intensity as the blood. A deviation of the ion intensity of the inventive calibration fluid from the value of the normal physiological ion intensity of the blood that is actually present is permissible with reference to an adequate potentiometric measuring precision as long as the ion intensity of the fluid remains in the range 155 mmol/lxc2x110 mmol/l.
When, in contrast, the ion intensity of the calibration fluid lies outside the range 155 mmol/lxc2x110 mmol/l, measuring errors can occur that falsify the potentiometric measured result.
Preferably and advantageously, the inventive calibration fluid is fashioned such that the ion types contained in the blood are present in concentrations in the fluid that deviate so little from the normal physiological concentrations of these ion types in the blood that, given a contact between the fluid and the blood, a diffusion voltage of less than 1 mV occurs at the boundary surface between the fluid and the blood.
This measure is based on the perception resulting from the Henderson equation (see Koryta, pages 21 f) that, given what is not a negligibly diffusion voltage between fluid and blood, this voltage acts as a measuring error at least where the calibration fluid is employed as a bridge electrolyte between a reference electrode and the blood and that this measuring error is negligible when the diffusion voltage is lower than 1 mV.
A diffusion voltage that is not negligibly high occurs at the boundary between fluid and blood when, for example, the ion composition of the fluid does not fall within the range of the normal physiological ion composition of the blood, whereby it already suffices when the concentration of only a single ion type of the fluid, for example, the Na+ ionsxe2x80x94lies adequately far outside the range of the normal physiological concentration of this ion type in the blood.
Preferably and advantageously, the inventive calibration fluid exhibits an osmolarity that lies in the range 295 mosmol/lxc2x120 mosmol/l into which the normal physiological range of the osmolarity of blood plasma falls. This has the advantage that the osmolarity of the fluid lies in the range of an osmolarity of a sensor for measuring a blood value and, consequently, no disturbing effects due to osmotic pressure differences occur given contact of the fluid with this sensor. It can be expedient to select a value for the osmolarity that lies optimally close to 295 mosmol/l.
The inventive fluid can advantageously comprise a pH value in the range between 6.6 and 8.0 which is advantageously greater than the range between 7.1 and 7.95 disclosed by EP 0 657 030 B1.
An especially advantageous and preferred embodiment of an inventive calibration fluid comprises a physiological organic buffer that is preferably defined by a specific Tris/TrisH+ ratio or by a specific R-PO42xe2x88x92/R-HPO4xe2x88x92 ratio. R stands for a selectable organic radical.
Like calibration fluids that are usually employed, the inventive calibration fluid is usually produced at room temperature (standard value 22xc2x0 C.) and stored thereat such that, at this temperature, it comprises a sum of all partial pressures that is equal to the pressure bearing on the fluid while being stored, this usually being the local atmospheric pressure (standard value 760xc2x7(4/3)xc2x7102 Pa=760 mmHg).
The calibration fluid is expediently heated to 37xc2x0 C. in the sensor means, for example in a full-through channel of this means, in order to assure a calibration of a sensor at the standard body temperature at which the blood values are also measured.
The heating of the calibration fluid from 22xc2x0 C. to 37xc2x0 C. in the sensor means ensues suddenly and without the possibility of a gas exchange with the ambient air. This results in a sudden increase in the sum of all partial pressures of the fluid.
When the elevated sum of all partial pressures of the fluid is higher than the pressure bearing on the fluid, this can lead to exhalation of gas from the fluid and to a formation of bubbles in the fluid. This is one possibility for the creation of gas bubbles that arise at the sensor itself and/or can be transported to the sensor with the fluid.
Another possibility for the creation of gas bubbles at the sensor is, for example, an inclusion of air or of some other gas in the calibration fluid and transport of this enclosed gas together with the fluid to the sensor.
A bubble pressure that is equal to the pressure bearing on the fluid at the sensor prevails in a gas bubble stuck to the sensor. Given sensor devices wherein the blood values are measured in vitro, this is usually equal to the pressure bearing on the fluid while being stored, usually the local atmospheric pressure; given sensor devices wherein the blood values are measured in vivo, this is usually equal to the pressure bearing on the fluid during storage plus the average blood pressure (approximately 100xc2x7(4/3)xc2x7102 Pa=100 mmHg) in the blood vessel that is in communication with the sensor.
Gas bubbles at the sensor during the calibration can lead to considerable calibration errors that produce uncontrollable measuring errors in a subsequent blood value measurement.
Given an inventive calibration fluid, the risk of a creation of calibration errors due to gas bubbles can be advantageously reduced in that the sum of all partial pressures of the fluid is lower than a pressure that bears on the fluid.
This measure advantageously assures that no gas bubbles arise in the fluid due to exhalation of gas of the fluid or assures that gas bubbles already present, for example enclosed air, disappear due to absorption in the fluid. This is also particularly true when the fluid for calibration of the sensor is preferably heated to 37xc2x0 C. at the sensor in order to assure a calibration at the standard body temperature.
The sum of all partial pressures of the fluid should at least be lower than the pressure that bears on the fluid at the sensor. This assures that gas bubbles cannot arise, at least at the sensor.
When, in this case, gas bubbles have arisen in the fluid at a location other than at the sensor and when these proceed to the sensor, on the other hand, they are absorbed by the fluid at the sensor and advantageously disappear by themselves, since, of course, the pressure bearing on the fluid at the sensor is higher than the sum of all partial pressures of the fluid.
Gas bubbles can arise in the fluid due to gas inclusion at the other location orxe2x80x94since the sum of all partial pressures of the fluid is higher than the pressure bearing on the fluid at this location, can arise due to exhalation of gases from the fluid.
An exhalation of gases from the fluid can be absolutely prevented when the sum of all partial pressures of the fluid is selected lower than the lowest pressure bearing on the fluid. In this case, gas bubbles due to exhalation of the fluid cannot arise anywhere in the fluid and gas bubbles that have arisen due to gas inclusion are immediately absorbed in the fluid and disappear not only at the sensor but everywhere, since the sum of all partial pressures of the fluid is lower everywhere than the pressure bearing on the fluid.
The sum of all partial pressures of the fluid is temperature-dependent and increases with increasing temperature. This temperature dependency must be taken in to consideration. The determining factor is the temperature prevailing at the sensor. It must be assured that the sum of all partial pressures of the fluid at the sensor at this temperature is lower than the pressure that bears on the fluid at the sensor.
The temperature prevailing at the sensor is the determining factor. It must be assured that the sum of all partial pressures of the fluid at this temperature at the sensor is lower than the pressure that bears on the fluid at the sensor.
The sum of all partial pressures of the inventive calibration fluid is composed at least of the partial pressure of a solvent, for example water, and a non-disappearing partial pressure pCO2 of the carbon dioxide.
It is advantageous when the partial pressure of the N2 at 37xc2x0 C. in the inventive calibration fluid is lower than the normal physiological value of this pressure in the blood at this temperature. The normal physiological value of the partial pressure of N2 in blood at 37xc2x0 C. amounts to about 573xc2x7(4/3)xc2x7102 Pa (537 mmHg).
This measure offers the following advantages: it is beneficial to select the sum of all partial pressures of the fluid optimally low compared to the pressure bearing on the fluid since an exhalation of gases of the fluid is all the more dependably prevented and an absorption of gas bubbles in the fluid is more assured the higher the difference between the higher, bearing pressure and the smaller sum of all partial pressures of the fluid is.
The partial pressure of the neutral blood gas N2 is, on the one hand, of no significance in the measurement of the blood values; on the other hand, its normal physiological value in the blood is higher than the sum of all other normal physiological partial pressures of the blood that are of significance for measuring the blood values and, for this reason, should also be present in the fluid for a calibration with a partial pressure value that differs from zero.
For this reason, it is expedient to effect the reduction of the sum of all partial pressures of the fluid mainly on the basis of a lowering of the partial pressure of N2.
It is especially advantageous to essentially entirely forego N2 in the fluid, so that the N2 partial pressure of the fluid is essentially equal to zero. In this case, the greatest possible difference between the pressure bearing at the sensor and the sum of all partial pressure of the fluid is advantageously achieved.
An inventive calibration fluid is preferably and advantageously employed as bridge electrode between a reference electrode and a measuring electrode in a potentiometric measuring instrument comprising a reference electrode and a measuring electrode for measuring a blood value.
The inventive calibration fluid, which differs from the traditional calibration fluid, cannot be produced from a traditional physiological electrolyte by simply adding the carbon dioxide source to this electrolyte. A preferred and advantageous method for simple production of the inventive calibration fluid is by dissolving a specific quantity of an essentially salt-free, aqueous solvent NaHCO3 together with at least one other biocompatible salt are of such a weight ratio relative to one another that the solution subsequently exhibits a bicarbonate ion concentration at 37xc2x0 C. in the normal physiological range of the blood, a pH value in a pH value range within 2 through 13 containing the value 7.41 and an ion intensity in the normal physiological range of the blood.
The inventive calibration fluid generally exhibits the following advantages:
The fluid enables a calibration of a sensor with a higher precision compared to the known calibration fluid, both in vivo as well as in vitro.
Since the ion intensity of the fluid is selected in the range 155 mmol/lxc2x110 mmol/l, a correct concentration result with respect to the blood can always be obtained.
Since the ion types contained in the blood are contained in the fluid in concentrations deviating so little from the normal physiological concentrations of these ion types in the blood that a diffusion voltage of less than 1 mV occurs at the boundary surface between the fluid and the blood given a contact between the fluid and the blood, this diffusion voltage is negligible and no measuring errors caused by diffusion voltage occur when the calibration fluid is employed as a bridge electrolyte between a reference electrode and the blood.
Since the concentration of the bicarbonate ions in the fluid lies in the range 24 mmol/lxc2x15 mmol/l, the effect is that the base excess of the blood is not negatively influenced by the fluid infused into the blood and, consequently, the base excess actually present in the blood can be measured unfalsified, regardless of whether it exhibits the normal physiological value lying at 0 mmol/l or an abnormal, positive or negative value.
The base excess is a metabolic characteristic of blood whose normal physiological value is equal to 0 mmol/l and that can deviate more or less greatly from 0 mmol/l given a metabolic disturbance. A base excess of the blood differing from 0 mmol/l is normalized very slowly via the kidneys, over a course of hours.
Due to the concentration of HCO3xe2x88x92 ions in the fluid being in the range 24 mmol/lxc2x15 mmol/l, no disturbance of the metabolic acid-base economy of the organism is advantageously produced given an infusion of the fluid, this disturbance being capable of being dismantled only very slowly via the kidneys.
The pH value of the fluid can deviate more greatly then previously from the normal physiological 7.41 of the blood. As a result thereof, the sensitivity of a pH value sensor can be advantageously identified in a greater range of measurement with two different pH values.
In particular, the pH value of the fluid in the entire range between 6.6 and 8.0 can advantageously be highly buffered compared to a bicarbonate buffer, so that it can be set with long-term stability. For example, the buffer effect to 20 mmol/l NaHCO3 is very slight because less than 0.3 mmol/l volatile CO2 are present in the fluid at 37xc2x0 C. By themselves, the 20 mmol/l NaHCO3 produce only a temporarily stable pH value.
The buffer system employed for intense buffering of the pH value of the fluid is physiologically innocuous when the fluid laced with this buffer system exhibits the concentration of CHO3xe2x88x92 ions lying in the range 24 mmol/lxc2x15 mmol/l. In this case, the blood with the infused, highly buffered fluid is rapidly brought to the normal physiological pH value of 7.41 and to the normal physiological pCO2 of 40xc2x7(4/3)xc2x7102 Pa (40 mmHg) of the blood by the respiratory system, i.e. after passing the lung once, even given a pronounced deviation of the pH value of the fluid from the normal pH value of 7.41. The normal physiological pCO2 is a respiratory characteristic of the blood.
The physiologic, organic buffers are especially suited for intense buffering of the fluid exhibiting the concentration of HCO3xe2x88x92 ions lying in the range 24 mmol/lxc2x15 mmol/l since they have the advantages that they can be innocuously infused.
The fluid is advantageously physiologically compatible for all patient groups and enables a high precision in the identification of the blood values.
The sum of all partial pressures of the fluid can be advantageously selected lower than the pressure bearing on the fluid at the sensor, so that no gas bubbles arise in the fluid or gas bubbles already present are absorbed in the fluid, these potentially highly falsifying the calibration of the sensor.
The sensors for measuring the following blood values can be advantageously calibrated with the fluid: pCO2, pH value and concentrations of all ion types contained in the blood or blood plasma such as HCO3xe2x88x92, Na+, K+, Ca2+, Mg2+, Clxe2x88x92, SO42xe2x88x92, CO32xe2x88x92, etc.